2. Academic Validation
  3. Unlocking the Hydrolytic Mechanism of GH92 α-1,2-Mannosidases: Computation Inspires the use of C-Glycosides as Michaelis Complex Mimics

Unlocking the Hydrolytic Mechanism of GH92 α-1,2-Mannosidases: Computation Inspires the use of C-Glycosides as Michaelis Complex Mimics

  • Chemistry. 2022 Mar 7;28(14):e202200148. doi: 10.1002/chem.202200148.
Santiago Alonso-Gil 1,  Kamil Parkan 2,  Jakub Kaminský 3,  Radek Pohl 3,  Takatsugu Miyazaki 4
Affiliations

Affiliations

  • 1 Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Dr.-Bohr-Gasse 9, 1030, Vienna, Austria.
  • 2 Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Technická 5, 166 28, Prague, Czech Republic.
  • 3 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Gilead Sciences & IOCB Research Centre, Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague, Czech Republic.
  • 4 Research Institute of Green Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka, 422-8529, Japan.
PMID: 35049087 DOI: 10.1002/chem.202200148
Abstract

The conformational changes in a sugar moiety along the hydrolytic pathway are key to understand the mechanism of glycoside hydrolases (GHs) and to design new inhibitors. The two predominant itineraries for mannosidases go via O S2 →B2,5 →1 S5 and 3 S1 →3 H4 →1 C4 . For the CAZy family 92, the conformational itinerary was unknown. Published complexes of Bacteroides thetaiotaomicron GH92 catalyst with a S-glycoside and mannoimidazole indicate a 4 C1 →4 H5 /1 S5 →1 S5 mechanism. However, as observed with the GH125 family, S-glycosides may not act always as good mimics of GH's natural substrate. Here we present a cooperative study between computations and experiments where our results predict the E5 →B2,5 /1 S5 →1 S5 pathway for GH92 Enzymes. Furthermore, we demonstrate the Michaelis complex mimicry of a new kind of C-disaccharides, whose biochemical applicability was still a chimera.

Keywords

carbohydrates; conformations; enzymology; inhibitors; quantum mechanics.

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